Thursday, March 24, 2011

I think that it might be a good idea to state here that I'm a calories-in calories-out sort of a person. Arguing about metabolic advantage is pointless. When a person loses weight they convert tissue to energy, amputations excepted. Where the calories go, whether it is BMR, thermogenesis, glycosuria, increased spontaneous movement, shivering etc, the calories always go somewhere. As far as I am aware no one is suggesting that calories evaporate. Certainly I'm not.

I am on blog as stating that dietary fat, in common with carbohydrate, is stored in the aftermath of a meal. If you did not store your dietary fat it would sit there in your chylomicrons until you were as hyperlipaemic as a diabetic on an ADA approved low fat diet. All fat which is not used for on going metabolism must be stored. It may take a few hours to clear chylomicrons but they do get cleared. Mostly in to adipocytes.

If you take a human like ET, who is maintaining a bodyweight of 142kg by eating 4,200kcal per day, you can adjust her macronutrient ratio to pretty well whatever you like and she will remain weight stable, provided you insist that she always consumes 4,200kcal/d. Insulin will plummet on a high fat diet and this will release necessary fatty acids from adipocytes. These FFAs, the Spawn of Satan, will be both released and used at an increased rate. But will she lose weight? Of course not. She will just re-pack her adipocytes with the extra fat from her fixed, 4,200kcal, low carbohydrate diet. Many people, myself included, can maintain weight stability on a low carbohydrate diet for years.

There's a nice paper about fat accumulation under low insulin conditions on my hard drive. It happens. I will post about it when I feel like it, it looks interesting.

There was one participant in the GnK study, RP, who refused to comply with the study protocol. That's a 20% non compliance rate. She under ate and lost weight. We get no information about her caloric intake at any stage. We know relatively little about her diet (ie sugar vs starch) before the study. We have no idea what sort of carbohydrate was used in the study diet. The only information we have about which phase of the diet gave the weight loss is this graph:

But we certainly have a failure of compliance in this study where an obese subject refused scheduled food and subsequently lost weight. That's worth remembering.

Now let's look at hypocaloric conditions in the same paper. DB, SM and DM were put on to 1,500kcal/d (Keysian starvation) from 2,200kcal/d, 3600kcal/d or 3,800kcal/d respectively. They, err, lost weight. They lost weight pretty nigh on linearly over 12 weeks whether their fasting insulin was 40microIU/ml or 15microIU/ml, produced by adjustment of their carbohydrate intake from 240g/d, down to zero and back to 240g/d.

NB I am perfectly willing to accept these results as they stand but just as an aside; none of the individual records shows any suggestion of a weight shift related to to glycogen depletion/repletion on these changes in carbohydrate intake. The LC phase included zero carbohydrate. The HC version of 1,500kcal provided 72% of calories as some sort of carbohydrate, ie 240g/d. Maybe even Weight Watchers depletes liver glycogen following an overnight fast... A bit odd but probably irrelevant.

Back to the results. The caloric intake was fixed and low. Fat was stored in the LC/HF group and accessed easily because insulin was low. Under high carbohydrate intake calories were stored mostly as glycogen and glucose was metered out to avoid hypoglycaemia. Any fat lost by the lower-but-not-zero rate of lipolysis under high insulin levels was simply not replaced.

Just eat 1,500kcal/d and you will lose weight. Eat more than 1,500kcal and you're a pig.

The study was designed to get exactly these results.

But, out of only five subjects, one obese person became a food refusenick. Various studies have had similar compliance problems, with obese participants refusing food. Let's look at some of them.

I knew there had been a paper by Krauss looking at lipoprotein subgroups during weight stability on assorted carbohydrate intakes. It didn't measure plasma insulin but, if we accept anything from GnK's work, I think we have to accept that under weight stability we can dial fasting insulin by adjusting carbohydrate intake. At least between 4% and about 72% of calories.

Krauss looked at diets composed of 54%, 39% or 26% of energy from carbohydrate, with a bonus group on 26% carbohydrate and (gasp) 15% of total calories as saturated fat.... These folks were instructed to maintain weight stability. This quote had the LC brigade, myself included, giggling if not rolling around in the aisles.

"Despite our effort to maintain constant weight, the 26%-carbohydrate, low-saturated-fat diet group lost more weight than did the 54%-carbohydrate group during the stable-weight period. There was also a trend for a greater reduction in percentage body fat with the lower-carbohydrate diets (P < 0.02, analysis of variance)."

My browser squishes the table, these are the numbers that matter, simplified. Remember, everyone was supposed to be weight stable:

Some of these numbers made p<0.05 or even <0.02, shrug. What is more interesting is the trend in accidental weight loss. Oh and look, the sat fat group didn't lose the most weight, just the most fat. I like that.

My take home message is that the lower the carbohydrate intake (and it is reasonable to assume the lower the fasting insulin) the harder it is to consume enough calories to maintain the obese state. It's possible, but not easy.

Then there is this study looking at the HPA stress axis under fixed calorie low carbohydrate or medium carbohydrate diet conditions. I'll just look at weight and insulin because the changes in the processing of cortisol are about as lucid as Krauss' early papers on lipoprotein changes due to dietary saturated fat. It seems reasonable to assume things improved on LC, otherwise any deterioration would have been headline news. This is a crossover study, the same people did a month on low carb and a month on medium carb, in random order. This makes the results tables somewhat unintelligible but it still comes close to replication the 1,500ckal section of GnK's paper.

Under weight stable conditions fasting insulin was 16.6microIU/ml on 57% carbohydrate. Under LC (4% carbs) conditions, on a fixed 2000kcal intake insulin dropped to 7.3microIU/ml. Weight loss was 7.2kg in 4 weeks. Eating 2000kcal of which 35% was carbs gave 4.7kg weight loss on a fasting insulin of 9.2microIU/ml. After correction for water shifts under LC there was exactly the fat loss accounted for by a caloric deficit of 66kcal/d. This was, oddly enough, exactly the caloric count of the food REFUSED from the 2000kcal provided during the LC phase........... Which they had been asked to eat. Obese people refusing part of a 2000kcal ration.

These folks where in a residential diet study. They consistently refused food they had agreed to eat during the "fixed" caloric intake phase, but only if the macronutrient ratio lowered insulin. As an aside the insulin level on LC was statistically significantly lower than on weight stability but the drop on medium carbohydrate was not. I would argue that the difference between either 7.3microIU/ml or 16.6microIU/ml and 9.2 microIU/ml is biologically significant even if p is > 0.05.

The original report details the menus and a battery of psychological test. There is a mass of information in this study from Aberdeen. As we all know, people mostly seem to get depressed and stoopid on LC diets. In this instance they just stopped being hungry!

Here is one of the best quotes, from the results section:

"The 3-d maintenance diet was designed to 1) neutralize the ketogenic state and replete liver carbohydrate stores and 2) to return hunger to baseline levels— equivalent to the maintenance period 1, before ad libitum feeding—recognizing that a carryover effect from the weight-loss phase existed. This design is particularly relevant for the subjects who were given the LC ketogenic diet first and then the MC nonketogenic diet."

"to return hunger to baseline levels......" I like that. Hunger on the ketogenic diet is not at baseline levels, it is lower. Just supplying MORE calories INCREASES hunger, so long as the calories have carbohydrate at 57%. Hungry and weight stable or less hungry while losing weight. I really like that.

Then a brief quote from this paper, also a weight loss rather than weight stability study, but the quote is too entertaining to leave out.

Fasting insulin was 11.6microIU/ml and 14.4microIU/ml at 3 and 6 months under ad libitum calories but progressively less stringent carbohydrate restriction. Under rigid calorie restricted low fat eating it was steady around 18microIU/ml.

"Based on dietary records, the reduction in daily caloric intake was similar in the two groups. For the greater weight loss in the very low carbohydrate group to be strictly a result of decreased caloric consumption, they would have had to consume approximately 300 fewer calories/d over the first 3 months relative to the low fat diet group (28). Although the inaccuracy of dietary records for obese individuals is well documented (31, 32), it seems unlikely that a systematic discrepancy of this magnitude occurred between groups of subjects who were comparably overweight."

We know that obese people always under report their caloric intake, just ask any obesity expert. Why on earth should this particular group of obese people consistently over report their caloric intake? That's not what fat people do.

You could rephrase this to speculate that the LC group either ate and "used" an extra 300kcal/d or became pathological liars who exaggerated their food intake by 300kcal/d, presumably to wind up the experimenters. Ketosis does make you stoopid and depressed, why shouldn't it make you in to a practical joker too?

Is anyone seeing a pattern of people (or rats) refusing food under reduced insulin conditions?

In the real world people eat when they are hungry, because they are hungry. They don't drink fixed caloric intakes of mysterious liquid formulations from researchers who's rat models are based on either sucrose or vegetable oil.

Can people actually gain weight on high fat diets? Of course they can. You can accumulate fat without elevated insulin. But you are much less likely to gain weight if you are not hungry.

I note that Chris Voight was not on a fixed calorie intake and was not hungry while he lost an impressive amount of his excess weight. I think his fasting insulin was low and he was performing lipolysis at an impressive rate.

Overfeeding in excess of preferred calorie intake breaks the system. GnK simply disabled the mechanism of appetite control by fixing caloric intake. Fine to prove a point. It's this sort of research that has got us where we are today.

NB I think this decrease in hunger probably only occurs in obesity. For those of us who have adopted a LC eating pattern without the need for weight loss (and still have little excess fat) there are clearly other factors coming in to play, as there will be when a previously overweight person approaches target/ideal weight, what ever that might be.

Saturday, March 19, 2011

You know how it is when CarbSane quotes a paper which refutes the carbohydrate hypothesis of obesity. You really can't be *rsed to chase it but you also know that there will be a fundamentally flawed approach which needs looking at. CarbSane was my route in to Kathleen Axen's work with transfats, which I've probably not finished with yet, but which markedly ramped up my dislike of these industrial lipotoxins. I really enjoyed digging back through the Axen papers, though it took hours, and there's no way I would have hit on them without CarbSane's dire (and incorrect) opinion of LC eating based on the last of the triad. Cracking.

So it is with Grey and Kipnis' paper on the irrelevance of fasting insulin to weight loss. It leads back to a rat paper (aren't you surprised!). The rat model was developed to allow rats to gain weight under hypoinsulinaemic conditions. So GnK had a high carbohydrate diet and a low carbohydrate diet for their rats, both of which promoted weight gain, but the LC diet did it without raised insulin. Here are the diets:

Nice.

But here's the funny part. They did a whole load of experiments (very interesting, seminal work on pancreatic glucokinase induction/suppression) which required equal calorie intake between a group on the high carbohydrate diet and another group on the zero carbohydrate diet. Let me quote:

"Since the low carbohydrate-high fat diet is less palatable to rats than the high carbohydrate diet, pair feeding was accomplished by determining the caloric intake of the low carbohydrate fed rats and then offering a comparable [ie less than they would have eaten] caloric amount of the high carbohydrate diet the following day to another group of animals."

You just have to admire the palate of those hypoinsulinaemic rats. Of course it's just possible they weren't ratty gourmands, it might actually be that they just weren't hungry because their fasting insulin was low and no one was ordering them to eat more than they felt like................

The giggles that come from following CarbSane's leads! Gotta get them from somewhere.

More on the cited Grey and Kipins 1971 paper when I've finished with the modern studies looking at the same question. There are some nice ones.

Tuesday, March 15, 2011

I'm not ready to post about this study yet but I thought I'd just put up a flag for its existence. It has long puzzled me why cholestryamine should show any benefit in cardiovascular disease, even if any benefit is offset by increased non cardiovascular mortality.

It turns out that cholestyramine increases the blood level of at least one oxysterol 25 fold. I would guess that this is accumulated in Lp(a).

This is of particular interest to me. I'll get around to why one day but thanks to Leib at THINCS for the lead in to the whole area.

So cholestyramine: When you look at all of the metabolic benefits which come with this wonder drug it's just amazing it doesn't save any lives.

Could it be that the multiple metabolic benefits (or the accumulated oxysterols, gasp, heresy again) reduce cvd mortality while the low cholesterol encourages you to throw a punch in some bar in down town Dallas?

I think it's pretty well established that free fatty acids are the Spawn of Satan.

This paper came my way through Luca and THINCS. Free fatty acids are just appalling. Read this paragraph from the discussion section and clutch at your chest:

"... studies have shown that a fat-enriched meal, in contrast to a high carbohydrate meal (HCM), is associated with endothelial activation [30] and may initiate injury to the blood vessel wall [31]. Increased circulating FFA and their derivatives have also been shown to be particularly deleterious on myocardial function during ischemia and reperfusion (for review see Ref. [32]). Indeed, in the ischemic myocardium, long-chain fatty acids accumulate quickly. The rate of fatty-acid uptake and oxidation by the heart is controlled by their availability [33]. Exogenous fatty acids, the main metabolic fuel of the myocardium under aerobic conditions, are detrimental during oxygen deprivation since their presence further augments the accumulation of long-chain acyl esters in the myocytes. The accumulation of lipids and their degradation products may contribute to the progression of injury. Furthermore, during reperfusion, fatty-acid oxidation can quickly recover and become the dominant source of ATP production. A high rate of fatty-acid oxidation contributes to a marked decrease in cardiac efficiency during the ischemia–reperfusion period [34]. We have previously shown that pharmacologically-induced increase in plasma FFA can significantly reduce the ischemic threshold in patients with stable coronary artery disease [35]. Recent studies have shown that FFA may also attenuate endothelium-dependent arterial vasodilatation [17,36] and increase sympathetic drive and alpha 1-adrenergic receptor reactivity and tone [37]. In addition, a HFM leads to an increase in calf vascular resistance [38]. All these data support a role for FFA and triglycerides both in vascular and muscular metabolic regulations."

I have to say that I've been through most of the references cited and many of them are quite hysterical. But that's another matter, maybe another post.

So the people who wrote the above paragraph had the bravery to feed a high fat meal, a high carbohydrate meal or nothing (on different days) to some cardiac patients and then treadmilled them to ST segment depression, ie until myocardial ischaemia set in. Obviously a high fat meal, particularly one based on saturated fat (as the test meal is claimed to have been, you don't get enough detail to tell what they used) should have crippled these people.

It didn't. The high fat meal had absolutely no effect on time to ischaemia.

How do they explain this? Easy, the high fat meal may have been a high fat meal, but it never raised plasma free fatty acids! This is what they say:

"However, this study was targeted to assess the role of a high fat meal and not of high serum FFA concentration; in fact due to the antilypolitic effect of the hyperinsulinemic response to the meal the serum FFA concentration was lower than in the fasting state."

Cunning hey? Just spike the high fat meal with exactly the correct amount of carbohydrate to lower lipolysis derived FFAs by an amount slightly more than the test meal generates and there is no overall change in FFAs (p > 0.05, ns) so no change in time to ischaemia! Beautifully done. But bollocks never the less.

Aside: Weird how you can use insulin to inhibit lipolysis in heart patients, just like treating ketoacidosis. You might almost imagine that insulin has something to do with weight control, I dunno... Back to the bollocks:

The same number of calories consumed as mostly carbohydrate dropped the time to ischaemia from 376 seconds to 297 seconds, p = 0.003, Table 2, line 13. This is despite the fact that carbohydrate meal reduced the Spawn of Satan from 0.89mmol/l to 0.27mmol/l, p = 0.002.

Of course with all that hard evidence about FFAs delaying myocardial recovery you really would expect an accelerated recovery from ST segment depression after the high carbohydrate meal, after all FFAs concentration is only a third of that under fasting conditions. In fact we can see from line 15 that the high carbohydrate meal gave a recovery time 30 seconds slower than after fasting, with all of that Spawn of Satan released from adipocytes due to not eating for a few hours. The high fat meal gave a recovery time which was 30 second faster. The spread in the numbers means that all of these differences are ns. No way can we tell how close p got to that good old 0.05, ns is all we get. But you really do have to wonder about how this fits in with all of those references in the above quote!

These authors do not go so far as to make dietary recommendations for folks with cardiovascular disease eager to spend a few minutes on a treadmill after supper.

Cardiologists back in the 1990s were not so reticent. This paper came out in 1996. It is essentially a poor man's version of the modern epic discussed above, with identical findings. What is the dietary advice if you have angina in Sheffield in 1996? Eat fat or carbohydrate before your jogging?

"It would be difficult to advise patients to take a higher proportion of calories as fat in the diet to minimize these early adverse cardiovascular effects, because of the potential effects of dietary fat on atherosclerosis genesis."

And the solution, just say no!

"...patients with angina should be advised to limit their activities in the early (first 30 min) postprandial period because of the reduction in angina threshold."

So if you are planning some post prandial exercise you can have an extra 79 seconds before myocardial ischaemic sets in by having cream instead of potatoes, but don't. Instead just put your feet up!

Sunday, March 06, 2011

I tried and failed to produce a comprehensive post about weight loss on an all potato diet. It runs to too many pages. This is a brief simplification.

Eating 2-3000kcal/day of potatoes spikes blood glucose. The more potatoes you eat the more you spike glucose. The pancreas responds to hyperglycaemia by secreting insulin but also by upregulating pancreatic glucokinase production, which increases insulin secretion per unit rise in glucose. After a couple of days on an all potato diet your pancreas will be producing impressive amounts of post prandial insulin.

Insulin is degraded by insulin degrading enzyme. Very, very, very crudely (with a ton of qualifications, read the paper!) insulin action leads to insulin degradation. All insulin sensitive tissues degrade insulin. The liver is a massive sink for insulin, especially on a high carbohydrate diet. Anything which increases hepatic insulin sensitivity should increase hepatic insulin degradation. A sudden ceasation of free fatty acid supply from adipocytes will increase both hepatic insulin sensitivity and hepatic insulin degradation. A potato diet supplies relatively little in the way of fatty acids so there is also little dietary fat to supply the lipid intermediates to encourage hepatic insulin resistance.

Much of the hepatic uptake of glucose occurs without the direct intervention of insulin. The liver has large numbers of GLUT2s on its cells, which allow insulin-independent hepatic glucose uptake via a simple concentration gradient. The gradient is maintained by the intracellular phosphorylation of glucose, which allows its prompt removal to metabolism or storage as glycogen. Hepatic glucokinase does this phosphorylation and the production of the glucokinase enzyme in the liver is, of course, controlled by insulin. Increased insulin leads to increased glucokinase production and enhanced GLUT2 mediated glucose uptake.

Without fat, bulk calories are stored as glycogen, excepting that there is a little de novo fat synthesis from glucose in the liver. Hepatic glycogen does not cause hepatic insulin resistance. In the near absence of FFA supply the liver maintains insulin sensitivity and the ability to degrade insulin. Nothing like as much insulin reaches the periphery as is produced by the pancreas in response to 2-3000kcal of potatoes.

The second effect of shutting down free fatty acid supply from adipocytes and diet is the loss of fatty acid intermediates in muscle. Insulin sensitivity increases, the amount of insulin needed to facilitate glucose uptake by muscles decreases. Insulin secretion from the pancreas will then decrease but hepatic extraction of insulin continues while ever carbohydrate adaption continues.

The ultimate determinant of weight loss is fasting insulin. This determines how much lipolysis occurs during the period before the next meal. No one expects to lose weight during the 4 hours immediately after any meal. The following 8 hours, especially overnight, is when weight loss occurs.

Post absorptively, without dietary glucose input, there is no stimulus for anything other than basal insulin secretion. Fasting insulin will be low because muscles are insulin sensitive so relatively little insulin is needed for glucose uptake. As fasting insulin levels drop lipolysis will restart. Free fatty acids will feed back to the liver to cause some degree of hepatic insulin resistance, decrease first pass metabolism and stop too profound an hypoinsulinaemia occurring. But fat loss will happen.

So you have to ask whether an almost all potato diet genuinely leads low fasting insulin and subsequent weight loss. For my perspective the answer is yes. The precedent for this has to the Kitavans with fasting insulin levels of 4.0microIU/ml.

The next question is whether anyone could do this. That, I suspect, depends on how broken your liver is, ie is there irreversible hepatic insulin resistance. If you are overweight secondary to simple fatty liver, which is completely reversible, I suspect the answer is yes. If you have pathology in your liver such as NASH, especially with fibrosis, I think you might not respond in the same way. The more of a problem you have with obesity the less likely you are to lose weight or experience appetite normalisation (translates as access to adipose tissue calories). Ultimately the ability to live on varied macronutrient ratios comes down to how broken you are, especially your liver. Why a broken liver requires low carbohydrate eating is another post.

Is it healthy for someone with a functional liver to live on potatoes? It is clearly possible in the medium term. Cooked tubers have a respectable history of human usage. If you are not broken it might be a reasonable diet. There are no trans fats in spuds. There are minimal omega 6 fats. There is no gluten. There is just enough fructose to activate hepatic glucokinase without generating de novo lipogenesis. There is adequate high quality protein. On the down side there are a stack of vitamin and mineral deficiencies waiting in the wings.

I have no doubt that Chris Voight lost weight on an all potato diet. I also have no doubt that he was neither chronically hyperglycaemic nor hyperinsulinaemic.

There is no way of putting numbers to the framework with the data I have at the moment, but the physiology is comprehensible.

OK, up for shredding.

Peter

There are a whole stack of follow on posts to this one but let's see how this one holds up first...

Tuesday, March 01, 2011

Ratty, about a year old, 410gm. Ad lib high fat diet, mostly portions of our food. Lots of lard, probably not diabetic! He is very, very strong for his size and can open the cage door after I bent the door clip tighter. Now he sleeps in rat Alcatraz overnight.

About Me

I am Petro Dobromylskyj, always known as Peter. I'm a vet, trained at the RVC, London University. I was fortunate enough to intercalate a BSc degree in physiology in to my veterinary degree. I was even more fortunate to study under Patrick Wall at UCH, who set me on course to become a veterinary anaesthetist, mostly working on acute pain control. That led to the Certificate then Diploma in Veterinary Anaesthesia and enough publications to allow me to enter the European College of Veterinary Anaesthesia and Analgesia as a de facto founding member. Anaesthesia teaches you a lot. Basic science is combined with the occasional need to act rapidly. Wrong decisions can reward you with catastrophe in seconds. Thinking is mandatory.
I stumbled on to nutrition completely by accident. Once you have been taught to think, it's hard to stop. I think about lots of things. These are some of them.

Organisation (or lack of it)!

The "labels" function on this blog has been used to function as an index and I've tended to group similar subjects together by using labels starting with identical text. If they're numbered within a similar label, start with (1). The archive is predominantly to show the posts I've put up in the last month, if people want to keep track of recent goings on. I might change it to the previous week if I ever get to time to put up enough posts in a week to justify it. That seems to be the best I can do within the limits of this blogging software!